Mindfulness and acceptance and commitment therapy for problematic alcohol use and disorders: an updated rapid review.

We updated systematic reviews for mindfulness and acceptance and commitment therapy for problematic alcohol use and disorders. We found growing evidence mindfulness was associated with reduced alcohol consumption and/or other therapeutic effects and was superior to other treatments under certain conditions. Mindfulness may be valuable for treating comorbidity and offer an alternative to traditional psychosocial interventions.

Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family.

We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors. One example of an early lead, OX01401, was found to inhibit PIMs with nanomolar potency (15 nM for PIM1), inhibit proliferation of two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, and to reduce intracellular phosphorylation of a PIM substrate in a concentration dependent manner.

Using a mobile health device to manage severe mental illness in the community: What is the potential and what are the challenges?

There has been a revolution in the use of mobile health devices for monitoring physical health. There is more recent interest in whether these devices can also be used for monitoring symptoms of mental illness. This paper considers how stress increases risk of mental deterioration and individuals with mental illness are sensitive to the effects of stress. It discusses how an inexpensive mobile health device could be used for detecting physiological signs of stress: deviations in biometrics such as sleep, activity and arousal may reflect a stress response and increased risk of relapse. These biometrics can allow patients to self-monitor and clinicians to detect early warning signs. This paper reviews the measurement of electrodermal activity, actigraphy and heart rate to predict mental deterioration. It considers the advantages of continuous measurement and reviews studies using mobile health devices to monitor stress and psychosis. It describes the potential for using a mobile health device to manage and monitor severe mental illness in young adults. Finally, this paper considers challenges associated with this approach, particularly with regard to correctly interpreting the physiological data and integrating the mobile health device into clinical practice. This paper concludes a mobile health device has the potential to enhance care by improving detection of early warning signs and increasing the connection between clinicians and their patients.

Systematic Reviews of Mindfulness and Acceptance and Commitment Therapy for Alcohol Use Disorder: Should we be using Third Wave Therapies?

AIMS: Third wave therapies have shown efficacy for treating emotional disorders and potential for treating substance use disorders. There is developing interest in whether they can more specifically be used for treating alcohol use disorders (AUDs). We were interested in whether third wave therapies have value alongside current evidence-based psychosocial treatments for AUDs. METHOD: We conducted systematic reviews of third wave therapies for AUDs. We searched PsycINFO, Embase and Medline for peer reviewed journal articles where mindfulness or Acceptance and Commitment Therapy (ACT) were used to treat adults with AUDs or alcohol use that caused impairment. RESULTS: We identified 11 studies where mindfulness was used for treating AUDs and 6 where ACT was used for AUDs. The studies identified included RCTs, non-randomized controlled studies and uncontrolled studies. We found preliminary support that both third wave therapies are better than no treatment, treatments of minimal efficacy, as well as some evidence they are comparable to effective psychosocial treatments for AUDs. CONCLUSIONS: We conclude ACT and mindfulness provide an alternative to existing treatments, particularly for patients who have not responded to, or have disengaged from, standard treatments. We also found some evidence ACT and mindfulness are useful for comorbid mental health conditions. Yet while these results are promising, further research is needed to determine their utility, ideally employing randomized-controlled designs, larger clinical samples and longer follow-ups. Furthermore, few studies in this review directly compared third wave therapies to first line treatments, making it difficult to determine their relative efficacy.

Cue Exposure Therapy for Alcohol Use Disorders: What Can Be Learned from Exposure Therapy for Anxiety Disorders?

Background: Cue Exposure Therapy (CET) has shown efficacy for treating alcohol use disorders (AUDs). Exposure therapy is highly effective for treating anxiety. Both techniques involve repeated, controlled exposures to alcohol or fear-related stimuli. Objectives: We considered the mechanisms of CET for AUDs by comparing it to exposure therapy for anxiety. Method: We conducted a narrative review contrasting theoretical literature examining the mechanisms of CET versus exposure therapy for anxiety. We reviewed RCTs and acute laboratory paradigms examining CET for AUDs. We considered common areas of emerging research, including the use of d-Cycloserine (DCS) and virtual reality (VR). Results: We found evidence that exposure therapy and CET at least partially achieve their effects through extinction learning. We found evidence that CET for AUDs is effective, with comparable benefits to other effective psychosocial treatments. DCS and VR have shown some limited success for augmenting CET for AUDs, so further research is needed to determine their value. Conclusions: There are theoretical and practical similarities between exposure to fear cues and cues of addiction, especially regarding extinction learning. However, these processes are also unique, particularly regarding the differing motivational properties of fear versus reward-related stimuli. We propose that unlike exposure for anxiety, CET takes effect by increasing self-control with each unreinforced exposure. We consider reasons for CET's limited use for AUDs, including its lower acceptability to clients and clinicians. We also note the limited evidence for CET for other substance use disorders, highlighting the need for continued investigation into its mechanisms and efficacy.

Translating Evidence-Based Practice for Managing Comorbid Substance Use and Mental Illness Using a Multimodal Training Package.

OBJECTIVE: Comorbid mental health and substance use problems are highly prevalent in substance use treatment settings and generally lead to poorer treatment outcomes. Pathways to Comorbidity Care (PCC) is a multimodal training program developed to encourage an integrated service approach to improve clinicians capacity to identify and manage comorbid substance use and mental health outcomes within public drug and alcohol treatment settings. METHODS: In this paper we describe the concepts underlying the PCC package and the use of implementation science to assess and overcome potential barriers, including clinicians preferences, knowledge about best practice, and professional culture. RESULTS: The training components include didactic seminars, group workshops run by a local clinical champion on relevant subjects such as motivational interviewing and cognitive behavioral therapy, individual clinical consultation, and feedback with a senior clinical psychologist. The PCC also includes an online portal containing comorbidity resources including manuals, guidelines, and booster webinars. Finally, we describe the evaluation of PCC implementation. CONCLUSIONS: Drug and alcohol services need to be equipped to treat the majority of comorbid mental health conditions in their clients. We anticipate that this multimodal training package, which applies the principles of implementation science, will facilitate effective and integrated care for these vulnerable clients.

Maternal Acceptance Moderates Fear Ratings and Avoidance Behavior in Children.

Avoidance is a hallmark feature of anxiety disorders, and avoidance-related impairment is often key to meeting diagnostic criteria. In children and adolescents with anxiety disorders, levels of avoidance vary considerably. Using a novel motion-tracking measure of avoidance behavior, we examined whether maternal acceptance, characterized by warm and accepting responses to child feelings and behaviors, moderates the association between fear of spiders and behavioral avoidance of spider stimuli in 103 clinically anxious children. As hypothesized, maternal acceptance significantly moderated children's avoidance behavior. Child's fear of spiders was significantly associated with behavioral avoidance when mothers were low in acceptance, as rated by either mothers or children. When mothers were high in acceptance, as rated by either mothers or children, child self-rated fear of spiders was not significantly associated with child avoidance. These are the first results to empirically demonstrate the moderating role of maternal acceptance in anxious children's avoidance behavior.

Correlates of Nonimprovement to Pharmacotherapy for Chronic, Antidepressant-Resistant, Military Service-Related Posttraumatic Stress Disorder: Insights From the Veterans Affairs Cooperative Study No. 504.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a chronic and often difficult-to-treat condition that is prevalent among military veterans. First-line pharmacotherapy for this population typically involves antidepressants; however, veterans who do not improve are sometimes prescribed antipsychotics such as risperidone. A 2011 randomized controlled trial of adjunctive risperidone versus placebo for veterans with chronic, antidepressant-resistant, military service-related PTSD revealed no difference between groups. Hence, there is a need to examine predictors of nonimprovement for chronic, treatment-resistant PTSD. METHODS: We examined correlates of nonimprovement and delayed improvement (ie, ≥12 weeks) using data from 267 veterans with chronic, antidepressant-resistant PTSD who were prescribed adjunctive risperidone or a placebo. Veterans received 1 to 4 mg adjunctive risperidone (n = 133; mean dose, 2.74 mg) or a placebo daily (n = 134) in addition to their original treatment regimen over the 24-week trial. RESULTS: Greater severity of PTSD symptoms at baseline, specifically reexperiencing (ie, nightmares) and emotional numbing (ie, sense of foreshortened future), was independently associated with nonimprovement. Of the 194 veterans (72.7%) who did improve, 95 (49.0%) showed delayed improvement, taking 12 weeks or longer to demonstrate a 10-point reduction in Clinician-Administered PTSD Scale scores. Emotional difficulties affecting role functioning, as assessed using the Veterans RAND 36-item Health Survey, independently predicted nonimprovement. CONCLUSIONS: While results are indicative of nonspecific pharmacotherapeutic effects, they suggest that specific PTSD symptom clusters and impairment are associated with variable improvement in veterans with antidepressant-resistant PTSD. They underscore the importance of developing more effective and targeted pharmacotherapies for specific symptom clusters in this population.

Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family.

The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75µM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition.

D-cycloserine enhances generalization of fear extinction in children.

BACKGROUND: For exposure therapy to be successful, it is essential that fear extinction learning extends beyond the treatment setting. D-cycloserine (DCS) may facilitate treatment gains by increasing generalization of extinction learning, however, its effects have not been tested in children. We examined whether DCS enhanced generalization of fear extinction learning across different stimuli and contexts among children with specific phobias. METHODS: The study was a double-blind placebo-controlled randomized controlled trial among dog or spider phobic children aged 6-14. Participants ingested either 50 mg of DCS (n = 18) or placebo (n = 17) before receiving a single prolonged exposure session to their feared stimulus. Return of fear was examined 1 week later to a different stimulus (a different dog or spider), presented in both the original treatment context and an alternate context. Avoidance and fear were measured with Behavior Approach Tests (BATs), where the child was asked to increase proximity to the stimulus while reporting their fear level. RESULTS: There were no differences in BAT performance between groups during the exposure session or when a new stimulus was later presented in the treatment context. However, when the new stimulus was presented in a different context, relative to placebo, the DCS group showed less avoidance (P = .03) and less increase in fear (P = .04) with moderate effect sizes. CONCLUSIONS: DCS enabled children to better retain their fear extinction learning. This new learning generalized to different stimuli and contexts.

Septicaemia models using Streptococcus pneumoniae and Listeria monocytogenes: understanding the role of complement properdin.

Streptococcus pneumoniae and Listeria monocytogenes, pathogens which can cause severe infectious disease in human, were used to infect properdin-deficient and wildtype mice. The aim was to deduce a role for properdin, positive regulator of the alternative pathway of complement activation, by comparing and contrasting the immune response of the two genotypes in vivo. We show that properdin-deficient and wildtype mice mounted antipneumococcal serotype-specific IgM antibodies, which were protective. Properdin-deficient mice, however, had increased survival in the model of streptococcal pneumonia and sepsis. Low activity of the classical pathway of complement and modulation of FcγR2b expression appear to be pathogenically involved. In listeriosis, however, properdin-deficient mice had reduced survival and a dendritic cell population that was impaired in maturation and activity. In vitro analyses of splenocytes and bone marrow-derived myeloid cells support the view that the opposing outcomes of properdin-deficient and wildtype mice in these two infection models is likely to be due to a skewing of macrophage activity to an M2 phenotype in the properdin-deficient mice. The phenotypes observed thus appear to reflect the extent to which M2- or M1-polarised macrophages are involved in the immune responses to S. pneumoniae and L. monocytogenes. We conclude that properdin controls the strength of immune responses by affecting humoral as well as cellular phenotypes during acute bacterial infection and ensuing inflammation.

Parent Versus Individual Cognitive Behavioral Therapy for Youth Anxiety: Protocol for an Overview of Systematic Reviews Over Time.

BACKGROUND: Cognitive behavioral therapy (CBT) has shown to be highly effective for treating youth anxiety; yet, there is ongoing debate as to whether involving parents improves outcomes. For example, parents who attend may learn CBT skills to help their child in an ongoing way; yet, they could also distract their child from treatment depending on how they interact. As evidence has accumulated, reviews and meta-analyses have attempted to examine the most effective treatment format. These reviews often have high impact in the field; however, they use varied methodologies and draw on different primary studies. Different formats of CBT for youth anxiety have been developed in relation to parental involvement, including youth-only CBT (Y-CBT; where the youth alone attends treatment), youth and parent or family CBT (F-CBT; where youths and their parents attend together), and, most recently, parent-only CBT (P-CBT; where the parent alone attends). OBJECTIVE: This protocol describes an overview of systematic reviews comparing the relative efficacy of different formats of CBT for youth anxiety (Y-CBT, F-CBT, and P-CBT) over the study period. The protocol will also examine the moderating effects of variables on the efficacy of different formats; for example, youths' age and long-term outcomes. METHODS: We will analyze the results of systematic reviews that compare different levels and types of parental involvement in CBT for youth anxiety over the study period. A systematic review of medical and psychological databases (PsycINFO, PubMed, SCOPUS, Web of Science, Cochrane Library, and Embase) will identify reviews comparing the efficacy of different formats of parent involvement in CBT for youth anxiety. Data extraction will include (1) author names (and year of publication), (2) review design, (3) age range, (4) analysis type, (5) conclusions, and (6) moderators. This overview will present the relative efficacy of formats chronologically in a table and then describe the main results longitudinally in a narrative summary. A Measurement Tool to Assess Systematic Reviews, 2nd Edition (AMSTAR 2), quality rating will be given to each review, and the amount of primary study overlap across reviews will be quantified. RESULTS: The last search was conducted on July 1, 2022. The reviews were published between 2005 and 2022. We found a total of 3529 articles, of which we identified 25 for the final analysis. CONCLUSIONS: This overview will compare and report the relative efficacy of Y-CBT, P-CBT, and F-CBT for youth anxiety over the study period, describe the heterogeneity across reviews and primary studies, and consider the moderating effect of relevant variables. It will describe the limitations of an overview, including the potential for nuance in the data to be lost, and provide conclusions and recommendations for conducting systematic reviews regarding parental involvement for CBT for youth anxiety. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/48077.

Using a mobile health device to monitor physiological stress for serious mental illness: A qualitative analysis of patient and clinician-related acceptability.

OBJECTIVE: There is growing interest in using mobile health (mHealth) devices to monitor physiological stress associated with mental deterioration. Research is currently examining whether physiological information returned to individuals with serious mental illness (SMI) and their clinicians enhances early intervention. The aim of this study was to explore patient and clinician-related acceptability of an mHealth device to monitor stress for SMI. METHOD: Individuals with SMI and their clinicians at a community youth mental health service were shown how an mHealth device could be used to monitor stress. Focus groups and interviews regarding the acceptability of the mHealth device were then conducted with participants (N = 22). Content was transcribed and analyzed using an inductive thematic analysis focusing on perceptions of potential benefit, barriers and facilitators of uptake. RESULTS: Six themes were identified. Individuals with SMI and clinicians identified two themes related to benefits of the mHealth device: (a) self-monitoring improves symptom insight and (b) clinician monitoring as a benefit to treatment. They identified one barrier theme: (c) privacy and data misuse concerns. They also identified three facilitators of uptake: (d) ease of use, (e) engaging design and (f) procedural guidelines. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The perceived benefits of passive physiological monitoring afforded by an mHealth device come with concerns regarding its privacy and the potential for ambiguity in the patient-clinician relationship. Results suggest the importance of codesign to ensure that it is secure, easy to use and engaging. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Staff experience, knowledge and attitudes regarding the management of adolescent patients in adult mental health units.

OBJECTIVE: Inpatient psychiatric care of adolescents should, where possible, be provided in specialized units. However, admission of adolescent patients to adult mental health units does occur. There is a paucity of data about this practice. This study collates information about the experience, attitudes and knowledge of clinical staff regarding the care of adolescent patients in adult psychiatry units within Northern Sydney Central Coast Area Health Service (NSCCHS). METHOD: A survey was emailed to all clinical staff with employer accessible email addresses in NSCCHS. RESULTS: The response rate was 29% (n = 108). The majority of respondents believed their wards were "not at all" (30.7%) or "only a little" (57.4%) equipped to care for adolescent patients. The majority felt "moderately" (39.6%) or "very" (16.8%) confident to care for these patients; however, a significant proportion (43.2%) lacked confidence. There was no significant difference across the responses of psychiatrists, psychiatry registrars and nursing staff to these questions. The majority felt the objectives of these admissions were met "only a little" (47.4%) or "not at all" (16.5%). Many concerns regarding the admission of adolescents to adult wards were reported. CONCLUSIONS: Generally, staff were not in favour of admitting adolescent patients to adult mental health units apart from in exceptional circumstances. Staff harboured concerns about several aspects of care for adolescents in adult wards.

Prevalence, risk correlates, and health comorbidities of insomnia in US military veterans: results from the 2019-2020 National Health and Resilience in Veterans Study.

STUDY OBJECTIVES: Veterans experience high levels of trauma, psychiatric, and medical conditions that may increase their risk for insomnia. To date, however, no known study has examined the prevalence, risk correlates, and comorbidities of insomnia in a nationally representative sample of veterans. METHODS: A nationally representative sample of 4,069 US military veterans completed a survey assessing insomnia severity; military, trauma, medical, and psychiatric histories; and health and psychosocial functioning. Multivariable analyses examined the association between insomnia severity, psychiatric and medical comorbidities, suicidality, and functioning. RESULTS: A total of 11.4% of veterans screened positive for clinical insomnia and 26.0% for subthreshold insomnia. Greater age and retirement were associated with a lower likelihood of insomnia. Adverse childhood experiences, traumatic life events, lower education and income were associated with greater risk for insomnia. A "dose-response" association was observed for health comorbidities, with increasing levels of insomnia associated with elevated odds of psychiatric and medical conditions (clinical vs no insomnia odds ratio = 1.8-13.4) and greater reductions in health and psychosocial functioning (clinical vs no insomnia Cohen's d = 0.2-0.4). The prevalence of current suicidal ideation was 3-5 times higher in veterans with clinical and subthreshold insomnia relative to those without insomnia (23.9% and 13.6% vs 4.5%, respectively). CONCLUSIONS: Nearly 2 in 5 US veterans experience clinical or subthreshold insomnia, which is associated with substantial health burden and independent risk for suicidal ideation. Results underscore the importance of assessment, monitoring, and treatment of insomnia in veterans as they transition from the military.

The hidden burden of social anxiety disorder in U.S. military veterans: Results from the National Health and Resilience in Veterans Study.

BACKGROUND: Social anxiety disorder (SAD) is a chronic and disabling psychiatric disorder associated with low levels of help-seeking. To date, however, scarce research has examined the epidemiology of SAD in veterans. This study examined the prevalence, comorbidities and incremental burden of SAD in relation to suicidality and functioning in a representative sample of U.S. military veterans. METHODS: A nationally representative sample of 3,157 U.S. veterans completed a web survey containing measures of SAD symptoms, trauma history, psychiatric history and functioning. Multivariable analyses were conducted to examine associations between SAD and psychiatric comorbidities, suicidality and functioning. RESULTS: A total 9.5% (n = 272) of the sample screened positive for lifetime SAD. Veterans with SAD were more likely than those without SAD to be younger, female, single, racial/ethnic minorities and to have experienced childhood abuse. They also had substantially elevated rates of comorbid psychiatric disorders, particularly lifetime major depression (odds ratio [OR]=5.8) and posttraumatic stress disorder (OR=3.1), as well as current suicidal ideation (OR=3.3). Veterans with SAD scored lower on measures of functioning, particularly social, emotional and mental health functioning (d's=0.21-0.34). LIMITATIONS: Data were collected cross-sectionally using self-report. CONCLUSIONS: SAD in U.S. veterans is prevalent and associated with psychiatric comorbidities, functional impairment and a more than 3-fold greater risk for suicidal ideation . Given that SAD is associated with low treatment seeking and engagement, it may be undetected and undertreated relative to other psychiatric morbidities. These results underscore the importance of screening, monitoring and treating SAD in this population along with other prevalent mental disorders.

Enantioselective desymmetrizing palladium catalyzed carbonylation reactions: the catalytic asymmetric synthesis of quaternary carbon center containing 1,3-dienes.

A desymmetrization protocol has been used to develop a palladium catalyzed enantioselective carbonylation process. Achiral cyclic bis-alkenyltriflates are converted to their corresponding monoester derivatives with selectivities of up to 96% ee.

Self-reported side effects in children and adolescents taking risperidone.

OBJECTIVE: We aimed to describe medication side effects in a cross-section of young people taking low-dose risperidone, using a self-report measure. METHODS: The Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) was completed by 66 patients aged between 6 and 18 years who had been taking low-dose risperidone (alone or in conjunction with other medications) for up to 13 years. RESULTS: Young persons, overall, seemed to tolerate risperidone well, but longer exposure to the medication was associated with higher side effect levels, particularly for the psychic (pertaining to mind and emotion) and extrapyramidal subscales. The most common complaints related to psychic side effects, such as tiredness, difficulty concentrating, difficulty remembering things and increased dreaming. CONCLUSIONS: Clinicians need to monitor the side effects of young patients taking low doses of risperidone, and other psychotropics, and maintain vigilance in those who have been taking medication for extended periods.

Integrating a Mobile Health Device Into a Community Youth Mental Health Team to Manage Severe Mental Illness: Protocol for a Randomized Controlled Trial.

BACKGROUND: Symptoms of mental illness are often triggered by stress, and individuals with mental illness are sensitive to these effects. The development of mobile health (mHealth) devices allows continuous recording of biometrics associated with activity, sleep, and arousal. Deviations in these measures could indicate a stressed state requiring early intervention. This paper describes a protocol for integrating an mHealth device into a community mental health team to enhance management of severe mental illness in young adults. OBJECTIVE: The aim of this study is to examine (1) whether an mHealth device integrated into a community mental health team can improve outcomes for young adults with severe mental illness and (2) whether the device detects periods of mental health versus deterioration. METHODS: This study examines whether physiological information from an mHealth device prevents mental deterioration when shared with the participant and clinical team versus with the participant alone. A randomized controlled trial (RCT) will allocate 126 young adults from community mental health services for 6 months to standard case management combined with an integrated mHealth device (ie, physiological information is viewed by both participant and case manager: unWIRED intervention) or an unintegrated mHealth device (ie, participant alone self-monitors: control). Participants will wear the Empatica Embrace2 device, which continuously records electrodermal activity and actigraphy (ie, rest and activity). The study also examines whether the Embrace2 can detect periods of mental health versus deterioration. A variety of measurements will be taken, including physiological data from the Embrace2; participant and case manager self-report regarding symptoms, functioning, and quality of life; chart reviews; and ecological momentary assessments of stress in real time. Changes in each participant's Clinical Global Impression Scale scores will be assessed by blinded raters as the primary outcome. In addition, participants and case managers will provide qualitative data regarding their experience with the integrated mHealth device, which will be thematically analyzed. RESULTS: The study has received ethical approval from the Western Sydney Local Health District Human Research Ethics Committee. It is due to start in October 2020 and conclude in October 2022. CONCLUSIONS: The RCT will provide insight as to whether an integrated mHealth device enables case managers and participants to pre-emptively manage early warning signs and prevent relapse. We anticipate that unWIRED will enhance early intervention by improving detection of stress and allowing case managers and patients to better engage and respond to symptoms. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000642987; https://www.anzctr.org.au/ACTRN12620000642987.aspx. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/19510.